A Review on The Protective Effects of Metformin in Sepsis-Induced Organ Failure

Despite advances in sepsis management, it remains a major intensive-care-unit (ICU) concern. From new prospective, positive effects of metformin, such as anti-oxidant and anti-inflammatory properties are considered potentially beneficial properties for management of septic patients. This article reviewed the potential ameliorative effects of metformin in sepsis-induced organ failure. Information were retrieved from PubMed, Scopus, Embase, and Google Scholar. Multi-organ damage, oxidative stress, inflammatory cytokine stimulation, and altered circulation are hallmarks of sepsis. Metformin exerts its effect via adenosine monophosphate-activated protein kinase (AMPK) activation. It improves sepsis-induced organ failure by inhibiting the production of reactive oxygen species (ROS) and pro-inflammatory cytokines, preventing the activation of transcription factors related to inflammation, decreasing neutrophil accumulation/infiltration, and also maintaining mitochondrial membrane potential. Studies reported the safety of metformin therapeutic doses, with no evidence of lactic acidosis, in septic patients.

[1]  H. Hamishehkar,et al.  Metformin-attenuated sepsis-induced oxidative damages: a novel role for metformin , 2018, Iranian journal of basic medical sciences.

[2]  D. Tang,et al.  AMPK regulates immunometabolism in sepsis , 2017, Brain, Behavior, and Immunity.

[3]  Guoji Zhu,et al.  Metformin ameliorates sepsis-induced brain injury by inhibiting apoptosis, oxidative stress and neuroinflammation via the PI3K/Akt signaling pathway , 2017, Oncotarget.

[4]  Daowen Wang,et al.  Liver Kinase B1/AMP-Activated Protein Kinase Pathway Activation Attenuated the Progression of Endotoxemia in the Diabetic Mice , 2017, Cellular Physiology and Biochemistry.

[5]  Ling Lin,et al.  Metformin attenuated endotoxin‐induced acute myocarditis via activating AMPK , 2017, International immunopharmacology.

[6]  Gengyun Sun,et al.  The alleviative effects of metformin for lipopolysaccharide-induced acute lung injury rat model and its underlying mechanism , 2017, Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society.

[7]  K. Carriere,et al.  Impact of Metformin Use on Lactate Kinetics in Patients with Severe Sepsis and Septic Shock , 2017, Shock.

[8]  N. S. Toutounchi,et al.  Metformin Alleviates Lipopolysaccharide-induced Acute Lung Injury through Suppressing Toll-like Receptor 4 Signaling. , 2016, Iranian journal of allergy, asthma, and immunology.

[9]  Maryam Rameshrad,et al.  AMPK activation by metformin inhibits local innate immune responses in the isolated rat heart by suppression of TLR 4-related pathway. , 2016, International immunopharmacology.

[10]  D. Cokkinos,et al.  Metformin protects against infection-induced myocardial dysfunction. , 2016, Metabolism: clinical and experimental.

[11]  Christopher W Seymour,et al.  Developing a New Definition and Assessing New Clinical Criteria for Septic Shock: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). , 2016, JAMA.

[12]  Maryam Rameshrad,et al.  Cardioprotective effect of metformin in lipopolysaccharide-induced sepsis via suppression of toll-like receptor 4 (TLR4) in heart. , 2016, European journal of pharmacology.

[13]  Adil Rafiq Rather,et al.  The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) , 2015 .

[14]  S. Efrati,et al.  Lactic acidosis and severe septic shock in metformin users: a cohort study , 2015, Critical Care.

[15]  Takla Griss,et al.  Metformin Antagonizes Cancer Cell Proliferation by Suppressing Mitochondrial-Dependent Biosynthesis , 2015, PLoS biology.

[16]  E. Abraham,et al.  AMP-Activated Protein Kinase and Glycogen Synthase Kinase 3β Modulate the Severity of Sepsis-induced Lung injury , 2015, Molecular medicine.

[17]  Amy R. Cameron,et al.  Anti-inflammatory effects of metformin and their relationship to the therapeutic action of the drug , 2015 .

[18]  L. Chao,et al.  Kallistatin protects against sepsis-related acute lung injury via inhibiting inflammation and apoptosis , 2015, Scientific Reports.

[19]  S. Bailey,et al.  Anti-inflammatory effects of four potential anti-endotoxaemic drugs assessed in vitro using equine whole blood assays. , 2015, Journal of veterinary pharmacology and therapeutics.

[20]  M. Uysal,et al.  Antidiabetic drug metformin is effective on the metabolism of asymmetric dimethylarginine in experimental liver injury. , 2014, Diabetes research and clinical practice.

[21]  J. Coppock,et al.  Dichloroacetate enhances apoptotic cell death via oxidative damage and attenuates lactate production in metformin-treated breast cancer cells , 2014, Breast Cancer Research and Treatment.

[22]  E. Bertini,et al.  Effects of levosimendan on mitochondrial function in patients with septic shock: a randomized trial. , 2014, Biochimie.

[23]  Jin-Tai Yu,et al.  Acute metformin preconditioning confers neuroprotection against focal cerebral ischaemia by pre‐activation of AMPK‐dependent autophagy , 2014, British journal of pharmacology.

[24]  J. Cha,et al.  Metformin Suppresses Lipopolysaccharide (LPS)-induced Inflammatory Response in Murine Macrophages via Activating Transcription Factor-3 (ATF-3) Induction* , 2014, The Journal of Biological Chemistry.

[25]  L. McCullough,et al.  Chronic metformin treatment improves post‐stroke angiogenesis and recovery after experimental stroke , 2014, The European journal of neuroscience.

[26]  Andrea Glasauer,et al.  Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis , 2014, eLife.

[27]  P. Pelosi,et al.  Oleanolic acid improves pulmonary morphofunctional parameters in experimental sepsis by modulating oxidative and apoptotic processes , 2013, Respiratory Physiology & Neurobiology.

[28]  J. Zmijewski,et al.  Metformin-stimulated AMPK-α1 promotes microvascular repair in acute lung injury. , 2013, American journal of physiology. Lung cellular and molecular physiology.

[29]  A. Esteghamati,et al.  Effects of metformin on markers of oxidative stress and antioxidant reserve in patients with newly diagnosed type 2 diabetes: a randomized clinical trial. , 2013, Clinical nutrition.

[30]  E. Abraham,et al.  Activation of AMPK Enhances Neutrophil Chemotaxis and Bacterial Killing , 2013, Molecular Medicine.

[31]  M. Radeos,et al.  Impact of metformin use on the prognostic value of lactate in sepsis. , 2012, The American journal of emergency medicine.

[32]  N. Chattipakorn,et al.  Effects of metformin on learning and memory behaviors and brain mitochondrial functions in high fat diet induced insulin resistant rats. , 2012, Life sciences.

[33]  Jin Sook Kim,et al.  Renal Podocyte Injury in a Rat Model of Type 2 Diabetes Is Prevented by Metformin , 2012, Experimental diabetes research.

[34]  Y. Azarmi,et al.  Study the effects of metformin on renal function and structure after unilateral ischemia-reperfusion in rat , 2012 .

[35]  H. Nasri.  Ameliorative effects of metformin on renal histologic and biochemical alterations of gentamicin-induced renal toxicity in Wistar rats , 2012, Journal of research in medical sciences : the official journal of Isfahan University of Medical Sciences.

[36]  B. Viollet,et al.  Cellular and molecular mechanisms of metformin: an overview. , 2012, Clinical science.

[37]  Jae Heun Lee,et al.  Metformin inhibits HMGB1 release in LPS‐treated RAW 264.7 cells and increases survival rate of endotoxaemic mice , 2011, British journal of pharmacology.

[38]  T. Espevik,et al.  Innate Immune Responses to Danger Signals in Systemic Inflammatory Response Syndrome and Sepsis , 2009, Scandinavian journal of immunology.

[39]  B. Casserly,et al.  The compensatory anti-inflammatory response syndrome (CARS) in critically ill patients. , 2008, Clinics in chest medicine.

[40]  M. Abdollahi,et al.  How does blood glucose control with metformin influence intensive insulin protocols? Evidence for involvement of oxidative stress and inflammatory cytokines , 2008, Advances in therapy.

[41]  M. Abdollahi,et al.  Clinical research Advantage of adjunct metformin and insulin therapy in the management of glycemia in critically ill patients. Evidence for nonoccurrence of lactic acidosis and needing to parenteral metformin , 2008 .

[42]  D. Herndon,et al.  Is there a role for metformin in the ICU , 2008 .

[43]  G. Bhamra,et al.  Metformin protects the ischemic heart by the Akt-mediated inhibition of mitochondrial permeability transition pore opening , 2008, Basic Research in Cardiology.

[44]  Takashi Kojima,et al.  Transmembrane proteins of tight junctions. , 2008, Biochimica et biophysica acta.

[45]  D. Pipeleers,et al.  Methyl succinate antagonises biguanide‐induced AMPK‐activation and death of pancreatic β‐cells through restoration of mitochondrial electron transfer , 2007, British journal of pharmacology.

[46]  P. Montravers,et al.  Effect of metformin on survival rate in experimental sepsis. , 2006, Diabetes & metabolism.

[47]  G. Arteel,et al.  Metformin Prevents Endotoxin-Induced Liver Injury after Partial Hepatectomy , 2006, Journal of Pharmacology and Experimental Therapeutics.

[48]  X. Leverve,et al.  Metformin prevents high-glucose-induced endothelial cell death through a mitochondrial permeability transition-dependent process. , 2005, Diabetes.

[49]  F. Finkelman,et al.  Bacterial Lipoprotein Delays Apoptosis in Human Neutrophils through Inhibition of Caspase-3 Activity: Regulatory Roles for CD14 and TLR-2 , 2004, The Journal of Immunology.

[50]  G. Jacobsen,et al.  Early lactate clearance is associated with improved outcome in severe sepsis and septic shock* , 2004, Critical care medicine.

[51]  Mitchell M. Levy,et al.  Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock , 2004, Critical care medicine.

[52]  K. Walley,et al.  Genetic polymorphisms in sepsis and septic shock: role in prognosis and potential for therapy. , 2003, Chest.

[53]  H. Kusuhara,et al.  Involvement of organic cation transporter 1 in the lactic acidosis caused by metformin. , 2003, Molecular pharmacology.

[54]  H. Redmond,et al.  Cutting Edge: Bacterial Lipoprotein Induces Endotoxin-Independent Tolerance to Septic Shock , 2003, The Journal of Immunology.

[55]  J. Lederer,et al.  The immunologic response to injury. , 2001, Journal of the American College of Surgeons.

[56]  G. Clermont,et al.  Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care , 2001, Critical care medicine.

[57]  E. Bilevicius,et al.  Multiple organ failure in septic patients. , 2001, The Brazilian journal of infectious diseases : an official publication of the Brazilian Society of Infectious Diseases.

[58]  S. Opal,et al.  Anti-inflammatory cytokines. , 2000, Chest.

[59]  T. Vary,et al.  TNF binding protein prevents hyperlactatemia and inactivation of PDH complex in skeletal muscle during sepsis. , 1998, The Journal of surgical research.

[60]  R. Bone,et al.  Immunologic Dissonance: A Continuing Evolution in Our Understanding of the Systemic Inflammatory Response Syndrome (SIRS) and the Multiple Organ Dysfunction Syndrome (MODS) , 1996, Annals of Internal Medicine.

[61]  M. Wilson,et al.  Free radical scavenging by lazaroids improves renal blood flow during sepsis. , 1996, Surgery.

[62]  C. Glueck,et al.  Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. , 1994, Metabolism: clinical and experimental.

[63]  R. Marfella,et al.  Metformin Improves Glucose, Lipid Metabolism, and Reduces Blood Pressure in Hypertensive, Obese Women , 1993, Diabetes Care.

[64]  W. Knaus,et al.  Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. , 1992, Chest.

[65]  R. Takayanagi,et al.  The Cardiovascular Effects of Metformin: Conventional and New Insights , 2014 .

[66]  Huan-huan Tian,et al.  [The effect of early goal lactate clearance rate on the outcome of septic shock patients with severe pneumonia]. , 2012, Zhongguo wei zhong bing ji jiu yi xue = Chinese critical care medicine = Zhongguo weizhongbing jijiuyixue.

[67]  T. van der Poll,et al.  Host-pathogen interactions in sepsis. , 2008, The Lancet. Infectious diseases.

[68]  X. Leverve,et al.  Neuroprotective Role of Antidiabetic Drug Metformin Against Apoptotic Cell Death in Primary Cortical Neurons , 2007, Journal of Molecular Neuroscience.